Remodeling of the left ventricle (LV), which includes dilatation, reduced contractile function, and, typically, increased fibrosis, is a major problem following myocardial infarction (MI) or severe pressure stress as one sees in advanced hypertension or valvular disease. Remodeling typically culminates in heart failure. Current therapeutics are inadequate, and while they can slow the progression of remodeling, the remodeling does inexorably progress. It is very clear that prevention of remodeling is an unmet need in cardiovascular disease. We have recently employed novel mouse models to identify critical roles for the GSK-3 family of protein kinases in remodeling post-MI and post-thoracic aortic constriction (TAC). In brief, deletion of the gene encoding GSK-3b is protective in the post-MI state. In stark contrast, deletion of the gene encoding GSK-3a leads to profound heart failure following either MI or TAC, due at least in part to markedly impaired b-adrenergic responsiveness. It is the purpose of this competing renewal application to extend our studies examining the role of the GSK-3 family in pathologic disease states in the heart. We plan to examine a very poorly understood issue: the role of the GSK-3 family in post-injury fibrosis, utilizing mouse models in which GSK-3a vs. GSK-3b is selectively knocked out in cardiomyocytes vs. fibroblasts. Our preliminary studies suggest that GSK-3a functions as a critical break on fibrosis. We will also identify the molecular mechanism by which GSK-3a regulates b-adrenergic responsiveness. The latter studies could lead to alternative strategies to traditional b-blockade, with the additional advantage that deletion (or inhibition) of GSK- 3a, unlike b-blockers, leads to improved glucose tolerance and insulin sensitivity.